Although the longevity-extending effects of Caloric restriction (CR) have been known for nearly 100 years and robustly proved in many species, its impact on public health is minimal because of difficulties with compliance. So both effectiveness and compliability are key to human adoption of any dietary strategy for functional longevity. We have identified a dietary strategy, the ketogenic diet (KD), that significantly extends cognitive memory, motor function and longevity (13%) over a standard diet. The KD is easier to comply with than CR, and in fact has been used as therapy for human neurological diseases for over 80 years. The KD extends longevity relative to a control diet even in the context of identical calories consumed, thus the longevity effect of the KD cannot be explained by a de facto CR. Our Aims are focused around 1) Increasing the functional compliability of the KD to ensure the broadest possible adoption and translation to humans while still maintaining functional effect. This will be done by testing the functional effects of intermittent KD strategies and a ketone ester supplement. 2) Uncovering the mechanism and biomarkers by which the isocaloric KD extends functional longevity, through RNAseq of tissues and blood, and looking for rescue in mouse models that lack critical targets through which the KD is thought to exert its effects including HCAR2 and Ffar3. 3) Lastly we will test the functional effects of intermittent KD strategies in PSAPP mice, as it was recently shown that 'genetically ketogenic' ShcKD mice resist PSAPP dependent neurodegeneration. The successful completion of these Aims will determine whether alternative KD strategies can increase functional longevity and provide resistance to Alzheimer's disease, and determine the underlying KD functional longevity mechanism.